title: BM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and thromboxane synthase.
abstract: Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2α) have recently received a lot of attention. This study aimed to investigate the effect of a dual thromboxane synthase inhibitor and thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB(2) synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF(2α). Our results show that a molecule combining receptor antagonism and thromboxane synthase inhibition is more efficient in delaying atherosclerosis in Apo E(-/-) mice than sole inhibition of TXA(2) formation.
authors.affiliation: Department of Cardiovascular Research, University of Liège, Belgium. ccherdon@ulg.ac.be
authors.forename: Céline
authors.initials: C
authors.lastname: Cherdon
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rolin
authors.forename: Julien
authors.initials: J
authors.lastname: Hanson
authors.forename: Annie
authors.initials: A
authors.lastname: Ooms
authors.forename: Laurence
authors.initials: L
authors.lastname: de Leval
authors.forename: Pierre
authors.initials: P
authors.lastname: Drion
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Natzi
authors.initials: N
authors.lastname: Sakalihassan
authors.forename: Jean-Olivier
authors.initials: JO
authors.lastname: Defraigne
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001241:Aspirin / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000517:prevention & control*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000166:cytology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012501:Saphenous Vein / Q000166:cytology; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C475768:N-terbutyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; D017482:Receptors, Thromboxane; D013453:Sulfonylurea Compounds; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C075750:8-epi-prostaglandin F2alpha; D013929:Thromboxane B2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D013930:Thromboxane-A Synthase; D001241:Aspirin